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TY - JOUR

T1 - Differential Sodium Current Remodelling Identifies Distinct Cellular Proarrhythmic Mechanisms in Paroxysmal vs Persistent Atrial Fibrillation

AU - Casini, Simona

AU - Marchal, Gerard A.

AU - Kawasaki, Makiri

AU - Fabrizi, Benedetta

AU - Wesselink, Robin

AU - Nariswari, Fransisca A.

AU - Neefs, Jolien

AU - van den Berg, Nicoline W. E.

AU - Driessen, Antoine H. G.

AU - de Groot, Joris R.

AU - Verkerk, Arie O.

AU - Remme, Carol Ann

N1 - Funding Information: This study was funded by 2 Innovational Research Incentives Scheme Vidi grants from the Netherlands Organisation for Health Research and Development (ZonMw 91714371 to C.A.R. and ZonMw 016.146.310. to J.R.G); a ZonMw Priority Medicines (PM-Rare) grant (113303006 to C.A.R.); the Netherlands CardioVascular Research Initiative CVON (PREDICT2 CVON2018-30 to C.A.R.). Publisher Copyright: © 2023 The Authors

PY - 2023/3

Y1 - 2023/3

N2 - Background: The cellular mechanisms underlying progression from paroxysmal to persistent atrial fibrillation (AF) are not fully understood, but alterations in (late) sodium current (INa) have been proposed. Human studies investigating electrophysiological changes at the paroxysmal stage of AF are sparse, with the majority employing right atrial appendage cardiomyocytes (CMs). We here investigated action potential (AP) characteristics and (late) INa remodelling in left atrial appendage CMs (LAA-CMs) from patients with paroxysmal and persistent AF and patients in sinus rhythm (SR), as well as the potential contribution of the “neuronal” sodium channel SCN10A/NaV1.8. Methods: Peak INa, late INa and AP properties were investigated through patch-clamp analysis on single LAA-CMs, whereas quantitative polymerase chain reaction was used to assess SCN5A/SCN10A expression levels in LAA tissue. Results: In paroxysmal and persistent AF LAA-CMs, AP duration was shorter than in SR LAA-CMs. Compared with SR, peak INa and SCN5A expression were significantly decreased in paroxysmal AF, whereas they were restored to SR levels in persistent AF. Conversely, although late INa was unchanged in paroxysmal AF compared with SR, it was significantly increased in persistent AF. Peak or late Nav1.8-based INa was not detected in persistent AF LAA-CMs. Similarly, expression of SCN10A was not observed in LAAs at any stage. Conclusions: Our findings demonstrate differences in (late) INa remodeling in LAA-CMs from patients with paroxysmal vs persistent AF, indicating distinct cellular proarrhythmic mechanisms in different AF forms. These observations are of particular relevance when considering potential pharmacologic approaches targeting (late) INa in AF.

AB - Background: The cellular mechanisms underlying progression from paroxysmal to persistent atrial fibrillation (AF) are not fully understood, but alterations in (late) sodium current (INa) have been proposed. Human studies investigating electrophysiological changes at the paroxysmal stage of AF are sparse, with the majority employing right atrial appendage cardiomyocytes (CMs). We here investigated action potential (AP) characteristics and (late) INa remodelling in left atrial appendage CMs (LAA-CMs) from patients with paroxysmal and persistent AF and patients in sinus rhythm (SR), as well as the potential contribution of the “neuronal” sodium channel SCN10A/NaV1.8. Methods: Peak INa, late INa and AP properties were investigated through patch-clamp analysis on single LAA-CMs, whereas quantitative polymerase chain reaction was used to assess SCN5A/SCN10A expression levels in LAA tissue. Results: In paroxysmal and persistent AF LAA-CMs, AP duration was shorter than in SR LAA-CMs. Compared with SR, peak INa and SCN5A expression were significantly decreased in paroxysmal AF, whereas they were restored to SR levels in persistent AF. Conversely, although late INa was unchanged in paroxysmal AF compared with SR, it was significantly increased in persistent AF. Peak or late Nav1.8-based INa was not detected in persistent AF LAA-CMs. Similarly, expression of SCN10A was not observed in LAAs at any stage. Conclusions: Our findings demonstrate differences in (late) INa remodeling in LAA-CMs from patients with paroxysmal vs persistent AF, indicating distinct cellular proarrhythmic mechanisms in different AF forms. These observations are of particular relevance when considering potential pharmacologic approaches targeting (late) INa in AF.

UR - http://www.scopus.com/inward/record.url?scp=85148744840&partnerID=8YFLogxK

U2 - 10.1016/j.cjca.2022.12.023

DO - 10.1016/j.cjca.2022.12.023

M3 - Article

C2 - 36586483

VL - 39

SP - 277

EP - 288

JO - Canadian journal of cardiology

JF - Canadian journal of cardiology

SN - 0828-282X

IS - 3

ER -